The September 11, 2001 terrorist attack on the World Trade Center (WTC) was an extraordinary environmental disaster containing an unprecedented combination of physical and emotional exposures to rescue and recovery workers. As a direct result, WTC disaster responders attending the WTC Health Programs (WTC-HP) exhibit persistent symptoms of post-traumatic stress disorder (PTSD) and respiratory illness linked to the severity of their exposures. Indeed, one-quarter of responders affected by these conditions suffer from both. Mental-physical comorbidity leads to increased disability and utilization of medical services. This proposal focuses on potential mechanisms underlying PTSD/respiratory comorbidity that may facilitate development of more effective, theory-driven interventions for these difficult to treat patients. The overall goal of this proposal is to explicate the mechanisms linking PTSD and lower respiratory symptoms (LRS) in WTC responders through an epigenetics approach. Given longitudinal findings from observational data on the pathway from WTC exposures to PTSD to respiratory illness and supportive biological data, ecogenomics is the logical next step for understanding immune dysregulation and thus increased persistence of symptoms over time. In the long-term, identification of biomarkers using the approach described in Uddin et al. may help to uncover new tools to genetically characterize different pathways to PTSD and respiratory illness in responders. The specific aims of study are: 1. to determine and compare the methylation pattern of the peripheral blood DNA of patients with WTC-PTSD, patients who never developed PTSD, and a non-traumatized healthy control group. We will also determine whether the methylation patterns observed in the WTC cohort are: comparable to findings from the Detroit-area community study (Uddin et al. 2010) similar for patients with chronic WTC-PTSD and those with PTSD in remission; and 2. To examine differences in methylation patterns among Long Island clinic responders with (a) comorbid WTC-PTSD and respiratory illness, (b) only respiratory illness, (c) only WTC-PTSD, and (d) neither respiratory illness nor WTC-PTSD. To accomplish these AIMS we will conduct whole-genome methylation assays on peripheral blood from these patients using the HumanMethylation450 BeadChip and Infinium assay and compare methylation patterns to identify biomarkers which differential the groups outlined in Aims 1 and 2. In addition, we will validate methylation differences in specific loci.